Antimicrobial Resistance in Major Gram-Positive Pathogens: Beyond the Vancomycin Border

Antimicrobial resistance (AMR) remains an ongoing and critical concern with substantial consequences for global public health. Although recent attention has focused on managing Gram-negative infections, Gram-positive pathogens contribute comparably to morbidity and mortality. The increasing prevalence of multidrug-resistant (MDR) Gram-positive infections has led to the widespread use of vancomycin and other next-line agents including linezolid, daptomycin, ceftaroline and dalbavancin. However, emerging resistance to these agents is increasingly reported, further limiting the available therapeutic options for Gram-positive infections. To this end, there is an urgent need for effective strategies to overcome resistance, including combination therapy, optimization of pharmacokinetic and pharmacodynamic parameters, and improved source control to reduce infection burden. Additionally, resistance surveillance, antimicrobial stewardship and the development of novel antimicrobials are warranted to address the rising threat of resistant Gram-positive infections. This review aims to provide an overview of resistance mechanisms in major Gram-positive pathogens and discuss existing and emerging approaches to overcome resistance to agents beyond vancomycin, incorporating recent evidence on combination therapies and providing a practical treatment algorithm.